Concise Synthesis of Valerena-4,7(11)-diene, a Highly Active Sedative, from Valerenic Acid

Abstract

A concise synthesis of valerena-4,7(11)-diene with potent sedative activity was achieved in three steps involving, reduction of carboxylic acid, bromination of the resulting alcohol, and reduction of the bromide from valerenic acid in a 63% total yield. This synthetic method makes it possible to provide further materials for biological testing to realize comprehensive SAR studies.Key words: valerena-4,7(11)-diene; valerenic acid; sedative activity; sesquiterpene Valerena-4,7(11)-diene ((2S,5R,6R)-5,9-dimethyl-2-(2-methyl-1-propenyl)bicyclo[4.3.0]non-1(9)-ene, 1) as shown in Fig. 1, has been isolated in a small quantity from the roots of Nardostachys chinensis 1,2) and Valeriana officinalis L., 3,4) and is a bicyclic sesquiterpene that has recently been shown to dose-dependently reduce the locomotor activity of mice with a particularly profound effect, the strongest sedative activity being observed at a dose of 0.06%. 1)The unique aspect for the pharmacological activity of this compound is that it can be administered via inhalation; the compound is naturally volatile at room temperature and bears a pleasant smell.1) It may hopefully be developed as a less-harmful remedy for attention deficit hyperactivity disorder (ADHD) and for the confused elderly. An efficient total synthesis of 1 therefore appears to be of importance, as more extensive and elaborate structural variations are envisaged. Structure-activity relationship (SAR) studies of this natural product would not only be able to elucidate the intrinsic mechanism of action, but would also open a new avenue for exploring the possible mode of action of this compound. However, an efficient method for synthesizing 1 is required before comprehensive SAR studies can become a reality.Valerenic acid 2, which has been isolated as the main component of Valeriana officinalis and previously synthesized by Mulzer et al. 5) and Altmann et al.,6) was purchased from EXTRASYNTHÈ SE (France) as an optically active compound (½ D À115 (c 0.13, CHCl 3 ). 2 has tranquilizing and/or sedative activity from animal experiments, 7) and the activation of adenosine receptors has been implicated in the action of valerian ingredients.8) We present here the first concise synthesis of valerena-4,7(11)-diene 1 from valerenic acid 2 as the starting material via the reduction of ,-unsaturated carboxylic acid to allylic alcohol with LiAlH 4 , bromination of the resulting primary alcohol with CBr 4 /PPh 3 , and reduction of the bromide with super hydride.Scheme 1 shows how the concise synthesis of target compound 1 was achieved in three steps from valerenic acid 2.Treatment of valerenic acid 2 with LiAlH 4 (LAH) at 0 C for 3 h gave valerenol 3 in a 93% yield without reduction of the conjugated olefin. 9) Alcohol 3 was reacted with triphenylphosphine and then exposed to tetrabromomethane at À10 C for 45 min to afford 4 in an 83% yield. Bromide 4 was converted to desired compound 1 as soon as possible since 4 easily decomposed. Bromide 4 was reacted with LiBHEt 3 at À20 C for 1 h to afford target...

Functional Identification of Valerena-1,10-diene Synthase, a Terpene Synthase Catalyzing a Unique Chemical Cascade in the Biosynthesis of Biologically Active Sesquiterpenes in Valeriana officinalis

“…This assignment was further verified by comparison to published spectral data of valerena-1,10-diene from Paul et al (11). Additionally, the oneand two-dimensional NMR data obtained for compound 2 (valerena-1,10-diene) isolated from V. officinalis root tissue, the VoTPS1 yeast-produced compound, and that prepared synthetically by Kitayama et al (31) were identical, as were the GC 1) and valerena-1,10-diene (2). Elucidating a Catalytic Mechanism for Valerenadiene Synthase-The biogenic origin of valerenadiene and other related sesquiterpenes has remained enigmatic due to the conceptual difficulties in chemically rationalizing the generation of an isobutenyl side chain at C-2 of 2.…”

Enzymatic synthesis of valerena‐4,7(11)‐diene by a unique sesquiterpene synthase from the valerian plant (Valeriana officinalis)

“…Therefore, instead of dodecane, a hydrophobic resin (Amberlite) was added to the yeast culture, and 0.7 mg of peak 4 was purified from the resin. When the purified product was analyzed by NMR, the chemical shifts from the 13 C-NMR perfectly matched those of the published NMR signals of valerena-4,7(11)-diene [28,29] (Table S2). However, 1 H-NMR data overlapped with other contaminants, making accurate integration and signal assignments very difficult.…”

“…2. Valerena-4,7(11)-diene was synthesized from valerenic acid according to the published protocol [28]. A detailed synthesis procedure is given in Doc.…”

Natural sesquiterpenoids

“…398 Another compound of this type valerena-4,7(11)-diene, a highly active sedative, has been synthesized starting from valerenic acid. 399 The sesquiterpenoid 558 has been isolated from an unidentified liverwort of the Gackstroemia genus. 250 A new aristolane sesquiterpene 559 has been found in the marine red alga Laurencia similis.…”